Human resistin protects against endotoxic shock by blocking LPS–TLR4 interaction

Abstract

Helminths trigger multiple immunomodulatory pathways that can protect from sepsis. Human resistin (hRetn) is an immune cell-derived protein that is highly elevated in helminth infection and sepsis. However, the function of hRetn in sepsis, or whether hRetn influences helminth protection against sepsis, is unknown. Employing hRetn-expressing transgenic mice (hTg) and recombinant hRetn, we identify a therapeutic function for hRetn in lipopolysaccharide (LPS)-induced septic shock. hRetn promoted helminth-induced immunomodulation, with increased survival of ()-infected hTg mice after a fatal LPS dose compared with naive mice or -infected hTg mice. Employing immunoprecipitation assays, hTg mice, and human immune cell culture, we demonstrate that hRetn binds the LPS receptor Toll-like receptor 4 (TLR4) through its N terminal and modulates STAT3 and TBK1 signaling, triggering a switch from proinflammatory to anti-inflammatory responses. Further, we generate hRetn N-terminal peptides that are able to block LPS proinflammatory function. Together, our studies identify a critical role for hRetn in blocking LPS function with important clinical significance in helminth-induced immunomodulation and sepsis.

An immune-cell signature of bacterial sepsis

“…Of note, the module in MS1 cells corresponding to mitochondrial respiration (MS1-A; MT-ND4, MT-CO3, MT-ATP6) correlated significantly with disease severity in sepsis patients from our primary cohort (Int-URO and URO, FDR = 0.03; Figure 2f), supporting the link between alterations in energy metabolism and immunoparalysis in sepsis 23 . In addition, a module of genes in MS1 related to anti-inflammatory and pro-resolving responses (MS1-B; S100A8, RETN, ALOX5AP, FPR2) [24][25][26] correlates negatively with severity (FDR = 0.04) ( Figure 2g, Extended Data Fig. 7g), consistent with a current model of sepsis wherein patients early in their disease have a heightened inflammatory state, but subsequently switch to an immunosuppressive state 27 .…”

Concurrent Immune Suppression and Hyperinflammation in Patients With Community-Acquired Pneumonia

“…Low TNF-α producers displayed higher levels of biomarkers associated with inflammation, i.e., pentraxin-3, (30) sTREM-1, (31) tenascin-C, (32) and TFF3, (33). Likewise, low TNF-α producers had higher plasma concentrations of resistin, a mediator linked with exacerbation of inflammation, (34,35) although more recent evidence has indicated an anti-inflammatory role for resistin in experimental sepsis (36). Another indication that the extent of immune suppression associates with the extent of hyperinflammation in CAP comes from the finding that low TNF-α producers had higher plasma levels of constituents of secondary granules (NGAL) and azurophilic granules (proteinase-3), products of neutrophils known to be highly expressed in response to inflammation (37,38).…”

Monocyte activation in systemic Covid-19 infection: Assay and rationale

“…Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74] . New or repurposed therapies may be able to modify the sequelae of severe infection.…”