Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Abstract

MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1−/− macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1−/− macrophages produced more proinflammatory cytokines such as TNF-α and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-α, IL-6, IL-10, and MIP-1α, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.

Regulation of innate immune response by MAP kinase phosphatase-1

“…Analysis of the lungs and livers of the mice have indicated that iNOS expression levels were substantially increased in LPS-challenged MKP-1 knockout mice relative to similarly treated wild-type mice (Zhao and Liu, unpublished observations). Additionally, in response to components of Staphylococcus aureus (a Grampositive bacteria), MKP-1 knockout mice also suffered more severe inflammatory injuries to a number of vital organs compared to wild-type mice [60]. Massive neutrophil infiltration, pulmonary edema, liver injury, and kidney dysfunction were also observed in the treated MKP-1 knockout mice [60].…”

“…Additionally, in response to components of Staphylococcus aureus (a Grampositive bacteria), MKP-1 knockout mice also suffered more severe inflammatory injuries to a number of vital organs compared to wild-type mice [60]. Massive neutrophil infiltration, pulmonary edema, liver injury, and kidney dysfunction were also observed in the treated MKP-1 knockout mice [60]. Consequently, MKP-1 knockout mice exhibited significantly elevated mortality relative to similarly treated wild-type mice [60].…”

“…Histological analysis of the livers revealed a marked increase in leukocyte infiltration in the vicinity of the bile ducts in LPS-challenged MKP-1 knockout mice, but not in similarly treated wild-type mice. Moreover, glycogen contents were lower in the livers of LPS-challenged MKP-1 knockout mice than in similarly treated wild-type mice, likely reflecting the dramatic decrease in food intake due to severe distress by these mice [60]. Kidney function was also impaired in the MKP-1 knockout mice challenged with LPS, whereas similarly treated wild-type mice exhibited normal kidney function [19].…”

Selective Roles of MAPKs during the Macrophage Response to IFN-γ

“…Members of the MKP family mediate dephosphorylation of threonine/serine and tyrosine residues within the MAPK activation motif, which is sufficient for total enzymatic inactivation (36). Other macrophage activating agents, such as LPS, induce strong levels of expression of MKP-1 (37) which contribute to attenuate proinflammatory responses mediated by LPS-induced MAPK activation (38,39). We hypothesize that repression of MKPs might be necessary to ensure adequate prolonged MAPK activity necessary for stabilizing transcripts involved in the biological response to IFN-␥.…”

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

“…Bacterial load or survival rates (when infected by Staphylococcus aureus) were reported to remain unaffected by the DUSP1 deletion, but the tissue damage and immune cell activation and recruitment were substantially potentiated (96). Similar to SHP-1, the DUSP1-mediated iNOS inhibition is also tightly synchronized with the up-regulation of competing arginase pathway.…”