Anatomic compartmentalization of a cytokine buffer system enables proinflammatory immune defense 3563

Abstract Description The mechanisms by which the immune system balances host protection with inflammation-induced tissue damage remain poorly defined. We investigated this concept in the context of the proinflammatory cytokine IL-6 during a murine viral infection. In the bloodstream, IL-6 is rapidly neutralized by a buffer system comprising a molar excess of the soluble IL-6 receptor (sIL-6R) and its co-receptor, gp130 (sgp130). Strikingly, we find that this buffering capacity is significantly reduced within the lung, allowing IL-6 to accumulate and propagate proinflammatory STAT3 signaling during infection. This propagation leads to potent immune responses and collateral tissue damage over millimeter-scale distances. Forced expression of the IL-6 buffer in the lung restricts proinflammatory signaling to the micrometer scale and substantially mitigates tissue damage. However, this intervention unexpectedly leads to viral accumulation and reduced host survival. Our findings reveal how compartmentalized cytokine buffering supports localized barrier defense while limiting systemic delivery of proinflammatory signals, and highlight how the spatial scales of immune responses control the trade-off between inflammation-induced damage and protective immunity. Funding Sources R01AI155447 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)