Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Abstract

Matrix metalloproteinase 7 (MMP7) is a member of the MMP family. In the small intestine, MMP7 is responsible for activating α-defensins, which are broad-spectrum anti-microbial peptides produced by the Paneth cells. We report that MMP7(-/-) mice are resistant to LPS-induced lethality and that this resistance is correlated with reduced levels of systemic cytokines. LPS induced the upregulation and activation of MMP7 in the small intestine, degranulation of the Paneth cells, and induction of intestinal permeability in MMP7(+/+) mice. In MMP7(-/-) mice, both LPS-induced intestinal permeability and consequent bacterial translocation to the mesenteric lymph nodes were reduced. Based on gene expression analysis and evaluation of intestinal damage, we attribute the protected state of MMP7(-/-) mice to reduced intestinal inflammation. Interestingly, we found that different α-defensins, namely Crp1 (DEFA1) and Crp4 (DEFA4), can stimulate IL-6 release in macrophages and ileum explants in a TLR4 independent way. We conclude that absence of MMP7 protects mice from LPS-induced intestinal permeability and lethality, and suggest that MMP7-activated α-defensins, in addition to their previously recognized bactericidal and anti-inflammatory roles, may exhibit pro-inflammatory activities in the intestine by activating macrophages and amplifying the local inflammatory response in the gut, leading to intestinal leakage and subsequent increase in systemic inflammation.

Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration

“…Loss of MMP-7 is also associated with an increased expression of several pro-inflammatory cytokines such as MCP-1, TNF-a, and RANTES in AKI (Figure 3), which regulate various aspects of inflammation and immunity. 45,46 Not surprisingly, induction of inflammatory cytokines is associated with an increased renal infiltration of CD3 þ T cells, CD45 þ leukocytes, and F4/80 þ macrophages (Figure 3). The mechanism by which MMP-7 inhibits inflammation remains to be elucidated, but it could be related to the degradation of FasL as well, because FasL also participates in the regulation of inflammation by an apoptosis-independent mechanism.…”

Passenger Mutations Confound Interpretation of All Genetically Modified Congenic Mice

“…Considering that Mmp7 -, Mmp8 -, and Mmp13 null mice are protected against LPS lethality (Vandenbroucke et al, 2013; Vandenbroucke et al, 2012; Vandenbroucke et al, 2014), we analyzed the contribution of the Casp11 inactivating passenger mutation in this phenotype. The closest Mmp gene to Casp11 is Mmp13 (<1 cM).…”

MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

“…Importantly, several expression studies have observed upregulation of multiple MMPs, including MMP-3, after an LPS challenge in different cell types and organs, and inhibition of MMPs via broad-spectrum MMP inhibitors clearly showed protection against endotoxic shock [13,71,72]. Furthermore, MMP-7, -8, -12 and -13 deficient mice were also previously reported to show protection against death and hypothermia in the systemic LPS mouse model [13,73,74,75]. Although NNGH is a potent inhibitor of MMP-3, it also blocks MMP-1, MMP-2, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, MMP-14, and MMP-20 activity.…”