AUTHOR=Chen Yanting , Lu Xiaohan , Whitney Raeann L. , Li Yu , Robson Matthew J. , Blakely Randy D. , Chi Jen-Tsan , Crowley Steven D. , Privratsky Jamie R. 

TITLE=Novel anti-inflammatory effects of the IL-1 receptor in kidney myeloid cells following ischemic AKI

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2024.1366259

DOI=10.3389/fmolb.2024.1366259

ISSN=2296-889X

ABSTRACT=<p><bold>Introduction:</bold> Acute kidney injury (AKI) is one of the most common causes of organ failure in critically ill patients. Following AKI, the canonical pro-inflammatory cytokine interleukin-1β (IL-1β) is released predominantly from activated myeloid cells and binds to the interleukin-1 receptor R1 (IL-1R1) on leukocytes and kidney parenchymal cells. IL-1R1 on kidney tubular cells is known to amplify the immune response and exacerbate AKI. However, the specific role of IL-1R1 on myeloid cells during AKI is poorly understood. The objective of the present study was to elucidate the function of myeloid cell IL-1R1 during AKI. As IL-1R1 is known to signal through the pro-inflammatory Toll-like receptor (TLR)/MyD88 pathway, we hypothesized that myeloid cells expressing IL-1R1 would exacerbate AKI.</p><p><bold>Methods:</bold> IL-1R1 was selectively depleted in CD11c<sup>+</sup>-expressing myeloid cells with <italic>CD11cCre</italic><sup><italic>+</italic></sup><italic>/IL-1R1</italic><sup><italic>fl/fl</italic></sup> (Myel KO) mice. Myel KO and littermate controls (<italic>CD11cCre</italic><sup><italic>-</italic></sup><italic>/IL-1R1</italic><sup><italic>fl/fl</italic></sup>–Myel WT) were subjected to kidney ischemia/reperfusion (I/R) injury. Kidney injury was assessed by blood urea nitrogen (BUN), serum creatinine and injury marker neutrophil gelatinase-associated lipocalin (NGAL) protein expression. Renal tubular cells (RTC) were co-cultured with CD11c<sup>+</sup> bone marrow-derived dendritic cells (BMDC) from Myel KO and Myel WT mice.</p><p><bold>Results:</bold> Surprisingly, compared to Myel WT mice, Myel KO mice displayed exaggerated I/R-induced kidney injury, as measured by elevated levels of serum creatinine and BUN, and kidney NGAL protein expression. In support of these findings, <italic>in vitro</italic> co-culture studies showed that RTC co-cultured with Myel KO BMDC (in the presence of IL-1β) exhibited higher mRNA levels of the kidney injury marker NGAL than those co-cultured with Myel WT BMDC. In addition, we observed that IL-1R1 on Myel WT BMDC preferentially augmented the expression of anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra/<italic>Il1rn</italic>), effects that were largely abrogated in Myel KO BMDC. Furthermore, recombinant IL-1Ra could rescue IL-1β-induced tubular cell injury.</p><p><bold>Discussion:</bold> Our findings suggest a novel function of IL-1R1 is to serve as a critical negative feedback regulator of IL-1 signaling in CD11c<sup>+</sup> myeloid cells to dampen inflammation to limit AKI. Our results lend further support for cell-specific, as opposed to global, targeting of immunomodulatory agents.</p>