Rochman et al. report proteomics of eosinophilic esophagitis, which identifies the minichromosome maintenance complex as a driver of esophageal basal zone hyperplasia. The cover image is an artistic rendering of minichromosome maintenance proteins in esophageal tissue. Image credit: Chris Woods, Mark Rochman, and Marc Rothenberg.
Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a BMAL1/CLOCK-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.
Stephen Kirchner, Vivian Lei, Paul T. Kim, Meera Patel, Jessica L. Shannon, David Corcoran, Dalton Hughes, Diana K. Waters, Kafui Dzirasa, Detlev Erdmann, Jörn Coers, Amanda S. MacLeod, Jennifer Y. Zhang
Many autoimmune diseases (AIDs) are characterized by persistence of autoreactive B cell responses which is often directly implicated in disease pathogenesis. How and why these cells are generated or how they are maintained for years is largely unknown. Rheumatoid arthritis is among the most common AIDs and characterized by autoantibodies recognizing proteins with post-translational modifications (PTMs). This PTM-directed, autoreactive B cell compartment is ill defined. Here, we visualized the B cell response against the three main types of PTM antigens implicated in RA by spectral flow cytometry. Our results showed extensive cross-reactivity of PTM-directed B cells against all three PTM antigens (citrulline, homocitrulline and acetyllysine). Unsupervised clustering revealed several distinct memory B cell (mBC) populations. PTM-directed cells clustered with the most recently activated, class-switched mBC phenotype, expressing high CD80, low CD24 and low CD21. Notably, patients also harbored large fractions of PTM-directed plasmablasts (PB). Both PTM-directed mBC and PB showed high expression of CXCR3, a receptor for chemokines abundantly present in arthritic joints. Together, our data provide detailed insight into the biology of B cell autoreactivity and its remarkable, seemingly exhaustless persistence in a prominent human AID.
Sanne Reijm, Joanneke C. Kwekkeboom, Nienke J. Blomberg, Jolien Suurmond, Diane Van der Woude, Rene E.M. Toes, Hans Ulrich Scherer
Host cytosolic sensing of Mycobacterium tuberculosis (M.tb) RNA by the RIG I-like receptor (RLR) family perturbs innate immune control within macrophages; however, a distinct role of MDA5, a member of the RLR family, in M.tb pathogenesis has yet to be fully elucidated. To further define the role of MDA5 in M.tb pathogenesis, we evaluated M.tb intracellular growth and innate immune responses in wild-type and Mda5-/- macrophages. Transfection of M.tb RNA strongly induced pro-inflammatory cytokine production in WT macrophages, which was abrogated in Mda5-/- macrophages. M.tb infection in macrophages induced MDA5 protein expression, accompanied by an increase in MDA5 activation as assessed by multimer formation. IFNγ-primed Mda5-/- macrophages effectively contained intracellular M.tb proliferation to a significantly greater degree than WT macrophages. Further comparisons of WT versus Mda5-/- macrophages revealed that during M.tb infection MDA5 contributes to IL-1β production and inflammasome activation, and that loss of MDA5 leads to a significant increase in autophagy. In the mouse TB model, loss of MDA5 conferred host survival benefits with a concomitant reduction in M.tb bacillary burden. These data reveal that loss of MDA5 is host-protective during M.tb infection in vitro and in vivo, suggesting M.tb exploits MDA5 to subvert immune containment.
C. Korin Bullen, Alok K. Singh, Stefanie Krug, Shichun Lun, Preeti Thakur, Geetha Srikrishna, William R. Bishai
Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries which undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate with the injury site. Subsequent single-cell RNA sequencing, molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury, potentially regulating immune cell production in the bone marrow, through delivery of endogenously produced itaconate and demonstrate a therapeutic potential for exogenous itaconate following tendon injury.
Janna l. Crossley, Sonya Ostashevskaya-Gohstand, Stefano Comazzetto, Jessica S. Hook, Lei Guo, Neda Vishlaghi, Conan Juan, Lin Xu, Alexander R. Horswill, Gerta Hoxhaj, Jessica G. Moreland, Robert J. Tower, Benjamin Levi
Background: Cardiorenal syndrome (CRS)—renal injury during heart failure (HF)—is linked to higher morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear. Methods: We investigated the role of circulating EVs from patients with CRS on renal epithelial/endothelial cells using a microfluidic kidney-on-chip model (KOC). The small RNA cargo of circulating EVs was regressed against serum creatinine to prioritize subsets of functionally relevant EV miRNAs and their mRNA targets investigated using in silico pathway analysis, human genetics, and interrogation of expression in the KOC model and in renal tissue. The functional effects of EV-RNAs on kidney epithelial cells were experimentally validated.Results: Renal epithelial and endothelial cells in the KOC model exhibited uptake of EVs from HF patients. HF-CRS EVs led to higher expression of renal injury markers (IL18, LCN2, HAVCR1) relative to non-CRS EVs. 15 EV-miRNAs were associated with creatinine, targeting 1143 gene targets specifying pathways relevant to renal injury, including TGF beta and AMPK signaling. We observed directionally consistent changes in the expression of TGF beta pathway members (BMP6, FST, TIMP3) in the KOC model exposed to CRS EVs, which were validated in epithelial cells treated with corresponding inhibitors and mimics of miRNAs. A similar trend was observed in renal tissue with kidney injury. Mendelian randomization suggested a role for FST in renal function. Conclusion: Plasma EVs in CRS patients elicit adverse transcriptional and phenotypic responses in a KOC model by regulating biologically relevant pathways, suggesting a role for EVs in CRS.
Emeli Chatterjee, Rodosthenis S. Rodosthenous, Ville J. Kujala, Priyanka Gokulnath, Michail Spanos, H. Immo Lehmann, Getulio P de Oliveira-Jr, Mingjian Shi, Tyne W. Miller-Fleming, Guoping Li, Ionita Ghiran, Katia Karalis, JoAnn Lindenfeld, Jonathan D. Mosley, Emily S. Lau, Jennifer E. Ho, Quanhu Sheng, Ravi Shah, Saumya Das
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