Macrophage inflammatory state influences susceptibility to lysosomal damage

Macrophages possess mechanisms for reinforcing the integrity of their endolysosomes against damage. This property, termed inducible renitence, was previously observed in murine macrophages stimulated with LPS, peptidoglycan, IFN gamma, or TNF alpha, which suggested roles for renitence in macrophage resistance to infection by membrane-damaging pathogens. This study analyzed additional inducers of macrophage differentiation for their ability to increase resistance to lysosomal damage by membrane-damaging particles. Renitence was evident in macrophages activated with LPS plus IFN gamma, PGE(2), or adenosine, and in macrophages stimulated with IFN-beta, but not in macrophages activated with IL-4 or IL-10. These responses indicated roles for macrophage subtypes specialized in host defense and suppression of immune responses, but not those involved in wound healing. Consistent with this pattern, renitence could be induced by stimulation with agonists for TLR, which required the signaling adaptors MyD88 and/or TRIF, and by infection with murine norovirus-1. Renitence induced by LPS was dependent on cytokine secretion by macrophages. However, no single secreted factor could explain all the induced responses. Renitence induced by the TLR3 agonist Poly(I:C) was mediated in part by the type I IFN response, but renitence induced by Pam3CSK4 (TLR2/1), LPS (TLR4), IFN gamma, or TNF alpha was independent of type 1 IFN signaling. Thus, multiple pathways for inducing macrophage resistance to membrane damage exist and depend on the particular microbial stimulus sensed.

Automated summary

Macrophages have mechanisms to enhance the integrity of their endolysosomes against damage, termed as inducible renitence. Multiple pathways exist for inducing macrophage resistance to membrane damage, depending on the particular microbial stimulus sensed, as observed in this study.