Inflammation
Abstract
Plasma membrane repair is critical for tissue integrity, especially for elongated contractile muscle cells. Genetically-mediated defects in plasma membrane resealing produce persistent leak, leading to a disordered extracellular matrix. Loss of the membrane repair protein dysferlin slows sarcolemmal resealing and promotes excess leak. Annexin A6 is also implicated in sarcolemmal repair, forming repair caps at the site of membrane disruption. On its own, deletion of the gene for annexin A6, Anxa6, had little effect on muscle health. In contrast, combined loss of dysferlin and annexin A6 (DysfA6) generated muscle fibers with profoundly defective membrane leak. Strikingly, Anxa6 deletion in the context of loss of dystrophin (mdxA6) did not exacerbate muscle defects. The persistent membrane leak in DysfA6 muscle resulted in marked macrophage infiltration with disordered macrophage polarization. Injured muscle fibers were targets of macrophage efferocytosis. Loss of Anxa6 was associated with increased expression of annexins A1 and A2, both of which were heavily deposited into the extracellular matrix. In vitro, macrophages exposed to annexins A1 and A2 increased Csf1 expression, consistent with a model where excess leak results in annexins A1 and A2 in the extracellular matrix, where this protein composition influences macrophage proliferation and efferocytosis.
Authors
GaHyun Lee, Alexander J. Fitt, Ashlee M. Long, Lauren A. Vaught, Dorothy DeBiasse, Alexander R. Keeble, Jason M. Kwon, Patrick G.T. Page, Marie-Therese Daher, Michele Hadhazy, Alexander B. Willis, David Ceja Galindo, Maxwell C. McCabe, Connor Lantz, Kirk C. Hansen, Rachelle H. Crosbie, Edward B. Thorp, Alexis R. Demonbreun, Elizabeth M. McNally
Abstract
Vaccine development for tuberculosis is a global priority. Our studies using Collaborative Cross (CC) mice show that genetic diversity influences the efficacy of BCG, the most widely used TB vaccine. BCG vaccination of CC042 mice reduced their lung bacillary burden and increased their survival following low-dose aerosol Mycobacterium tuberculosis infection (MTBI), despite impaired T cell trafficking due to a defective Itgal gene. BCG vaccination conferred early bacillary control which appeared to be independent of B cell or T cell recall responses following MTBI. In contrast, long term survival of BCG-vaccinated CC042 mice after MTBI required T cells. Thus, CC042 mice reveal two phases of immunity induced by BCG: an early phase mediated by innate immunity or innate-like T cells and a later phase mediated by conventional memory CD4 and/or CD8 T cells. Although measurement of vaccine-induced protection 30 days after MTBI is a standard measure of vaccine efficacy in the TB model, this time point might be independent of memory T cells in CC042 mice. Our results suggest that vaccine-elicited innate/innate-like responses could have a larger role in protection than previously considered. The concordance between lung CFU, pathology, and survival make CC042 mice useful for mechanistic studies on vaccine-induced immunity.
Authors
Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Anthony V. Tran, Gillian L. Beamer, Samuel M. Behar
Abstract
Polymorphonuclear neutrophils (PMNs) serve as frontline defenders against injury and infection, eliminating pathogens and initiating mucosal tissue repair. However, excessive PMN transepithelial migration (TEpM) contributes to chronic mucosal inflammatory disorders, including inflammatory bowel disease. PMN pro-inflammatory and pro-repair functions are regulated by incompletely defined signaling cascades involving kinases and phosphatases. Here, we determined how the protein tyrosine phosphatase CD45/PTPRC regulates PMN trafficking and effector functions in the gut. Pharmacologic inhibition of CD45 significantly reduced PMN colonic TEpM in vitro and in vivo and decreased intestinal PMN trafficking was observed in transgenic mice with PMN-specific deletion of CD45 (MRP8-Cre;Cd45fl/fl). Beyond limiting TEpM, CD45 depletion impaired key antimicrobial functions, including degranulation and phagocytosis, indicating broader effects on PMN effector activity. Importantly, recovery from dextran sodium sulfate (DSS)–induced colitis and biopsy-induced colonic wounding was delayed in MRP8-Cre;Cd45fl/fl mice, linking altered PMN function to defective mucosal healing. Mechanistically, CD45 depletion reduced surface expression of the β2 integrin CD11b/CD18 and inactivated the Src family kinase member Lyn. Together, data highlight an important CD45–CD11b–Lyn signaling axis that regulates PMN trafficking and effector functions in the intestine and identify CD45 as a promising target for modulating PMN function to promote mucosal tissue repair.
Authors
Jael Miranda, Dylan J. Fink, Zachary S. Wilson, Roland Hilgarth, Asma Nusrat, Charles A. Parkos, Jennifer C. Brazil
Abstract
Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined, and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza, and SARS-CoV-2–driven pneumonia. Our analysis revealed highly pneumonia type–specific proteomic signatures, including COVID-19–specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V–domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry–driven autoantibody profiling in 2 independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.
Authors
Anna Semenova, Taylor A. Poor, Johannes B. Müller-Reif, Sai Rama Sridatta Prakki, Phillip Geyer, Martin Mück-Häusl, Rogan A. Grant, Luke Rasmussen, Lesca M. Holdt, Daniel Teupser, Matthias Mann, Ali Ö. Yildirim, Richard G. Wunderink, Alexander V. Misharin, Ben D. Singer, G.R. Scott Budinger, Theodore S. Kapellos, Herbert B. Schiller
Abstract
Fibroblasts in the lung mesenchyme produce growth factors and extracellular matrix components that guide formation of distal airspaces during the saccular stage of lung development. Inflammation in preterm infants disrupts this process, leading to bronchopulmonary dysplasia (BPD). To examine how mesenchymal inflammation contributes to BPD pathogenesis, we developed a transgenic mouse model (“IKKβTbx4”) in which expression of activated human IκB kinase beta (IKKβ), an upstream activator of NF-κB, was induced in Tbx4 lung enhancer-positive mesenchymal cells during the saccular stage of lung development (postnatal day 0 [PN0] - PN5). Saccular stage IKKβTbx4 mice exhibited a BPD-like phenotype with interstitial thickening and reduced distal airspaces at PN5, progressing to emphysematous enlargement of the distal lung at 2 mo of age. Mesenchymal NF-κB activity upregulated the chemokines CCL2 and CCL7, recruiting CCR2pos monocyte-derived macrophages to the lung. Recruited macrophages disrupted the elastin scaffold and impaired microvascular organization with reductions in CAP2 endothelial cells (aCaps) and pericytes. Blocking CCR2-dependent monocyte recruitment with a small molecule CCR2 antagonist rescued the abnormal lung phenotype. These findings identify mesenchyme-macrophage crosstalk as a mechanism by which inflammation disrupts saccular stage lung development, suggesting a role for this signaling axis in BPD pathogenesis.
Authors
Benjamin C. Crawford, Jessica Chauviere Lee, Bertha C. Elias, Shivangi Dave, Riet van der Meer, Wei Han, Alexandria L. Sharkey, David S. Nichols, Charles Shissias, Lauren Pate, Hayden Tan, Dawn C. Newcomb, Wei Shi, Lawrence S. Prince, Erin J. Plosa, Bradley W. Richmond, Timothy S. Blackwell, Susan H. Guttentag, John T. Benjamin
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, yet the molecular basis underlying this variability remains incompletely understood. We profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n=207 SLE, n=45 HVs) and validation sets (n=53 SLE, n=41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering delineated correlated protein modules, including an interferon-associated module and a renal-associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes: positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti-RNP68, anti-RNP-A) was associated with increased interferon-stimulated protein levels (e.g., MX1, ISG15, CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the neutrophil protease proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular phenotypes, and provide a basis for precision medicine.
Authors
Geoffrey H. D. Leung, Charlotte Bottomley, Norzawani Buang, Robert T. Maughan, Benjamin J. Whittle, Boroumand Zeidaabadi, Yun-Ju Huang, Tabitha Turner-Stokes, Marie Condon, Liz Lightstone, Tom Cairns, Marina Botto, Matthew C. Pickering, James E. Peters
Abstract
Virally suppressed people with HIV (PWH) remain at risk for developing comorbidities due to chronic inflammation with one potential contributor being the HIV reservoir. Associations between the CD4-reservoir and inflammation have been extensively characterized, while the role the monocyte-reservoir is poorly understood despite evidence that inflammatory monocytes play a role in HIV-associated comorbidities. Additionally, most studies focus on a single cellular reservoir, while it is highly likely that these reservoirs are interdependent. In a cohort of 164 PWH, we used the intact proviral DNA assay to quantify cell-specific reservoirs, applied unsupervised clustering to identify reservoir phenotypes, and then determined if reservoir phenotypes were associated with distinct immune signatures compared to people without HIV. Five unique reservoir clusters emerged driven primarily by variability in the monocyte reservoir, and each associated with a distinct immune landscape. These included profiles characterized by systemic inflammation, leukocyte–vascular activation, T cell activation with vascular and neuronal injury, enhanced CD8 activation and NK cell recovery, and altered monocyte survival, activation, and migration. This multidimensional approach provides a framework to identify reservoir-immune profiles that may explain heterogeneity in inflammation despite viral suppression and may inform strategies to mitigate HIV-associated comorbidities.
Authors
Ruoyu Wang, Aparna B. Bhattacharyya, Lily Pohlenz, Erin N. Shirk, Hayley S. Romero, Katherine Haas, Jennifer M. Coughlin, Raha M. Dastgheyb, Leah H. Rubin, Rebecca T. Veenhuis
Abstract
Acute kidney injury (AKI) is a common and fatal complication of severe pneumonia, yet the mechanisms linking pulmonary inflammation to remote kidney injury remain poorly understood. Multicenter cohort data (n = 300) revealed that the incidence of severe pneumonia–associated AKI (SP-AKI) was 53.6%, with a mortality rate of 24.2%. SP-AKI was associated with elevated circulating levels of HMGB1, NETs, and IL-33. Murine experiments demonstrated that alveolar HMGB1 triggers the formation of IL-33–enriched NETs, which migrate to the kidney and activate tubular ST2/NF-κB signaling, driving inflammation and apoptosis. Genetic knockout of IL-33, ST2, or the NET-forming key enzyme PAD4, as well as pharmacological inhibition of HMGB1, IL-33, or NETs, all attenuated lung and kidney injury. Exogenous HMGB1 amplified NET-mediated IL-33 release, establishing a self-sustaining HMGB1/NET/IL-33 feed-forward loop. PAD4 deficiency completely blocked NET generation and disrupted HMGB1/IL-33 signaling. This study identified and validated a damage-associated molecular pattern–driven (DAMP-driven) HMGB1/NET/IL-33 signaling axis that mediates remote kidney injury in SP-AKI, redefining NETs from local effectors to cross-organ pathogenic carriers, thereby providing potential DAMP-targeted therapeutic avenues for SP-AKI.
Authors
Mengqing Ma, Hao Zhang, Weijuan Deng, Xia Du, Mengxing Chen, Dawei Chen, Binbin Pan, Zhaowei Wang, Ting Chen, Caimei Chen, Xin Wan, Changchun Cao
Abstract
Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology and the leading cause of acquired heart disease among children. Complement activation has long been observed in patients with acute KD, however, its contribution to disease development remains unknown. Here, using publicly available datasets, we showed that patients with acute KD exhibited higher expression of complement products in whole blood, consistent with the activation of the complement pathway. Similarly, in the Lactobacillus casei cell wall extract (LCWE) murine model of KD, LCWE injection induced increased expression of complement products in cardiovascular tissues, suggestive of activation of the complement pathways. C3-deficient mice or WT mice treated with the complement C5a Receptor 1 (C5ar1) antagonist developed significantly more severe LCWE-induced cardiovascular lesions and vasculitis. Furthermore, we observed that LCWE binds to serum C3, an opsonizing factor that labels microbial targets for clearance, and LCWE deposition in the liver was significantly higher in C3-deficient mice compared to WT mice. Overall, our data indicate that blocking the complement system significantly exacerbates LCWE-induced KD vasculitis, likely by impairing C3-mediated clearance of LCWE. These data suggest that the complement pathway may play a protective role in KD pathogenesis by promoting clearance of potential bacterial or viral trigger of KD.
Authors
Asli E. Atici, Begüm Kocatürk, Benjamin L. Ross, Emily A. Aubuchon, Rebecca A. Porritt, Thacyana T. Carvalho, Takahiro Namba, Youngho Lee, Magali Noval Rivas, Moshe Arditi
Abstract
Eosinophilic esophagitis (EoE) is a type 2 allergic disease characterized by esophageal inflammation and epithelial cell dysfunction. The acquired loss of the anti-serine protease of kazal type 7 (SPINK7) in the squamous epithelium of the esophagus has a causal role in EoE pathogenesis. Yet there is a limited understanding of the factors that regulate its expression and responsiveness to inflammatory stimuli. Herein, we have identified the transcription factor, ovo like transcriptional repressor 1 (OVOL1) as an esophageal selective gene product that regulates SPINK7 promoter activity. Overexpression of OVOL1 increased SPINK7 expression, whereas its depletion decreased SPINK7 expression, impaired epithelial barrier and increased production of the pro-atopy cytokine thymic stromal lymphopoietin (TSLP). Stimulation with IL-13 abrogated the nuclear translocation of OVOL1 and promoted enhanced degradation of OVOL1 protein. This effect of IL-13 was dependent on the esophageal specific cysteine protease calpain-14 at least in part. Analysis of human esophageal biopsies demonstrated that the expression of esophageal OVOL1 correlated with SPINK7 transcript expression and was lost as a function of EoE disease activity. In summary, our study identifies key regulatory mechanisms in EoE pathogenesis, demonstrating that OVOL1 promotes SPINK7 transcription, whereas IL-13 suppresses this pathway in EoE.
Authors
Nurit P. Azouz, Andrea M. Klingler, Sierra S. Beach, Kalen A. Rossey, Mark Rochman, Misu Paul, Julie M. Caldwell, Michael Brusilovsky, Alexander T. Dwyer, Xiaoting Chen, Daniel Miller, Carmy Forney, Leah C. Kottyan, Matthew T. Weirauch, Marc E. Rothenberg
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