Date of Award

12-15-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Yuan Liu

Second Advisor

Andrew Gewirtz

Third Advisor

Didier Merlin

Abstract

The immune system not only eliminates pathogens and other untoward factors but effectively does so without incurring host-compromising collateral damage. Among the many leukocytes buttressing this balancing act,macrophages reside at the helm of innate immunity and orchestrate finely tuned immune responses by acquiring a phenotype bespoke to the underlying inflammatory insult, the optimal result of which is the swift removal of noxious stimuli and reversion to homeostasis thereafter. On rare occasion, macrophages become hyper-activated and potentiate inflammation that often proves life-threatening rather than life-saving, as is the case in hemophagocytic lymphohistiocytosis (HLH) and other cytokine storm syndromes (CSS). Improving our understanding of the mechanistic bases by which macrophage phenotypic plasticity and function are regulated in health and disease will better inform the diagnosis and management of these often-fatal disorders of inflammation. In our study, we explore the role of signal regulatory protein alpha (SIRPɑ) in pro-inflammatory macrophage activation under toll-like receptor (TLR) 9 agonist-driven secondary HLH (S-HLH) and cytokine storm. We show that depleting SIRPα (SIRPα-/-) in mice during TLR9-driven inflammation exacerbates and accelerates the onset of fulminant S-HLH, in which hemophagocytosis, hypercytokinemia, cytopenias, hyperferritinemia, and other HLH hallmarks were apparent. In contrast, mice expressing SIRPα, including those deficient of the SIRPαligand CD47 (CD47-/-), do not phenocopy SIRPαdeficiency and fail to fully develop S-HLH. Although interferon gamma (IFNγ) is largely considered a driver of HLH pathology, IFNγ neutralization did not prevent the precipitation of S-HLH in TLR9-inflamed SIRPα-/- mice, whereas macrophage depletion attenuated S-HLH in SIRPα-/- mice. Mechanistic studies confirmed that SIRPα not only restrains macrophages from acquiring a hemophagocytic phenotype, but also tempers their pro-inflammatory cytokine and ferritin secretion by negatively regulating Erk1/2 and p38 activation downstream of TLR9 signaling. In addition to TLR9 agonists, TLR2, TLR3 or TLR4 agonists, as well as TNFα, IL-6, or IL-17A, but not IFNγ, similarly induced S-HLH in SIRPα-/- mice but not SIRPα+ mice. The collective findings of this study suggest that CD47-dependent and CD47-independent SIRPɑ inhibition play a negative role in HLH pathogenesis by precluding macrophages from becoming hemophagocytic and hyper-activated under inflammation.

DOI

https://doi.org/10.57709/26662457

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