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Necrosis Driven Triglyceride Synthesis Primes Macrophages for Inflammation During
Mycobacterium tuberculosis Infection
#MMPMID30018616
Jaisinghani N
; Dawa S
; Singh K
; Nandy A
; Menon D
; Bhandari PD
; Khare G
; Tyagi A
; Gandotra S
Front Immunol
2018[]; 9
(?): 1490
PMID30018616
show ga
Pulmonary tuberculosis (TB) exhibits granulomatous inflammation, a site of
controlling bacterial dissemination at the cost of host tissue damage. Intrigued
by the granuloma type-dependent expression of inflammatory markers in TB, we
sought to investigate underlying metabolic changes that drive amplification of
inflammation in TB. Here, we show an association of higher inflammation in
necrotic granulomas with the presence of triglyceride (TG)-rich foamy
macrophages. The conspicuous absence of these macrophages in solid granulomas
identified a link between the ensuing pathology and the metabolic programming of
foamy macrophages. Consistent with in vivo findings, in vitro infection of
macrophages with Mycobacterium tuberculosis (Mtb) led to increase in TG synthesis
only under conditions of ~60% necrosis. Genetic and pharmacologic intervention
that reduced necrosis prevented this bystander response. We further demonstrate
that necrosis independent of Mtb also elicits the same bystander response in
human macrophages. We identified a role for the human enzyme involved in TG
synthesis, diacylglycerol O-acyltransferase (DGAT1), in this phenomenon. The
increased TG levels in necrosis-associated foamy macrophages promoted the
pro-inflammatory state of macrophages to infection while silencing expression of
diacylglycerol O-acyltransferase (DGAT1) suppressed expression of
pro-inflammatory genes. Our data thus invoke a role for storage lipids in the
heightened host inflammatory response during infection-associated necrosis. Our
data provide a functional role to macrophage lipid droplets in host defense and
open new avenues for developing host-directed therapies against TB.
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