Small molecule–based inhibition of MEK1/2 proteins dampens inflammatory responses to malaria, reduces parasite load, and mitigates pathogenic outcomes

Xianzhu Wu,Kiran K Dayanand,Ramesh P Thylur,Christopher C Norbury,D Channe Gowda

doi:10.1074/jbc.m116.770313

Xianzhu Wu, Kiran K Dayanand + Show 3 more

Open Access

https://doi.org/10.1074/jbc.m116.770313

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Abstract

Malaria infections cause several systemic and severe single- or multi-organ pathologies, killing hundreds of thousands of people annually. Considering the existing widespread resistance of malaria parasites to anti-parasitic drugs and their high propensity to develop drug resistance, alternative strategies are required to manage malaria infections. Because malaria is a host immune response-driven disease, one approach is based on gaining a detailed understanding of the molecular and cellular processes that modulate malaria-induced innate and adaptive immune responses. Here, using a mouse cerebral malaria model and small-molecule inhibitors, we demonstrate that inhibiting MEK1/2, the upstream kinases of ERK1/2 signaling, alters multifactorial components of the innate and adaptive immune responses, controls parasitemia, and blocks pathogenesis. Specifically, MEK1/2 inhibitor treatment up-regulated B1 cell expansion, IgM production, phagocytic receptor expression, and phagocytic activity, enhancing parasite clearance by macrophages and neutrophils. Further, the MEK1/2 inhibitor treatment down-regulated pathogenic pro-inflammatory and helper T cell 1 (Th1) responses and up-regulated beneficial anti-inflammatory cytokine responses and Th2 responses. These inhibitor effects resulted in reduced granzyme B expression by T cells, chemokine and intracellular cell adhesion molecule 1 (ICAM-1) expression in the brain, and chemokine receptor expression by both myeloid and T cells. These bimodal effects of the MEK1/2 inhibitor treatment on immune responses contributed to decreased parasite biomass, organ inflammation, and immune cell recruitment, preventing tissue damage and death. In summary, we have identified several previously unrecognized immune regulatory processes through which a MEK1/2 inhibitor approach controls malaria parasitemia and mitigates pathogenic effects on host organs.

Highlights

Malaria infections cause several systemic and severe single- or multi-organ pathologies, killing hundreds of thousands of people annually
By using P. berghei ANKA (PbA)-infected C57BL/6 mice, an established model of experimental cerebral malaria (ECM) [23, 24], we studied the immunomodulatory effects of inhibitors of MEK1/2, the kinases immediately upstream of ERK1/2 in the signaling cascade, on immune responses to malaria and ECM pathogenesis
To determine the immunomodulatory role of MEK1/2 in severe malaria pathogenesis, we targeted these kinases by using small-molecule inhibitors and analyzed parasite growth kinetics, clinical episodes, and survival of the host in the mouse CM model

Summary

Results

To determine the immunomodulatory role of MEK1/2 in severe malaria pathogenesis, we targeted these kinases by using small-molecule inhibitors and analyzed parasite growth kinetics, clinical episodes, and survival of the host in the mouse CM model. Immunohistochemical analysis of brain sections showed higher levels of ICAM-1 in the vascular beds of control mice than that in PD-treated mice (Fig 11, C and D) Consistent with these results, numbers of CD11a (LFA-1)-expressing CD4ϩ T and CD8ϩ T cells were significantly lower in the brains of PDtreated mice (Fig. 11E and supplemental Fig. S5). The number of granzyme Bϩ cytotoxic CD8ϩ T cells was markedly lower in the brains of PD-treated mice than in control mice (Fig. 11F) Together, these results showed that MEK1/2 inhibitor treatment prevents brain pathology by reducing infiltration of inflammatory myeloid cells and cytotoxic T cells

Discussion

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