Macrophages monitor tissue osmolarity and induce inflammatory response through NLRP3 and NLRC4 inflammasome activation

W. K. Eddie Ip & Ruslan Medzhitov

Nat. Commun. 6:6931 doi: 10.1038/ncomms79311 (2015)

Speaker: Fu-Yu Chan (詹復宇)                          Time: 15:10~16:00

Commentator: Dr. Pin Ling (凌斌 老師)                  Place: Room 601

Abstract

Nod-like receptors (NLRs), including pyrin domain containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4), are important imflammasomes in inflammatory responses to sense hyperosmotic stress. Interstitial osmolality is a key homeostatic variable that varies depending on the tissue microenvironment. Mammalian cells have effective mechanisms to cope with osmotic stress by engaging various adaptation responses. Hyperosmolality due to high dietary salt intake has been linked to pathological inflammatory conditions. However, little is known about the mechanisms of sensing the hyperosmotic stress by the innate immune system. In this study, the authors reported that caspase-1 is activated in macrophages via NLRP3 and NLRC4 under hypertonic conditions. Mice with high dietary salt intake display enhanced induction of the Th17 response upon immunization, and this effect is abolished in caspase-1-deficient mice. The authors’ findings identify an unknown function of the inflammasome as a sensor of hyperosmotic stress, which is crucial for the induction of inflammatory Th17 response. The authors provide evidence for an inflammasome-dependent innate immune response to hyperosmotic stress and suggest that both NLRP3 and NLRC4 act to sense hyperosmolality of tissue microenvironment and mediate inflammatory responses, including neutrophil recruitment and adaptive Th17 responses. 

References

1.     Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821-832 (2010).

2.     Burg, M. B., Ferraris, J. D. & Dmitrieva, N. I. Cellular response to hyperosmotic    stresses. Physiol. Rev. 87, 1441-1474 (2007).