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Mycobacterium tuberculosis Lipoarabinomannan Activates Human Neutrophils via a TLR2/1 Mechanism Distinct from

Jessica S Hook1, Mou Cao1, Kayson Weng1

  • 1Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390; and.

Journal of Immunology (Baltimore, Md. : 1950)
|December 25, 2019
PubMed

Insights

Mycobacterium tuberculosis lipoarabinomannan (Mtb LAM) activates neutrophils via TLR2/1, inducing cytokine release but not classical priming responses seen with other TLR2 agonists. This suggests differential signaling localization.

Area of Science:

  • Immunology
  • Microbiology
  • Cell Biology

Background:

  • Neutrophils (polymorphonuclear leukocytes, PMN) are crucial for innate immunity against Mycobacterium tuberculosis (Mtb).
  • Interactions between PMN and Mtb lipids influence immune responses and tissue inflammation.
  • The role of Mtb lipoarabinomannan (Mtb LAM) in PMN activation and priming requires further elucidation.

Purpose of the Study:

  • To investigate whether Mtb LAM primes human PMN in a Toll-like receptor 2 (TLR2)-dependent manner.
  • To compare Mtb LAM's effects with synthetic TLR2 agonists, Pam3CSK4 and FSL-1.
  • To determine the signaling pathways and cellular responses elicited by Mtb LAM in PMN.

Main Methods:

  • Human PMN were stimulated with Mtb LAM, Pam3CSK4, and FSL-1.
  • Assessed PMN priming phenotypes: NADPH oxidase activity, l-selectin shedding, CD11b mobilization.
  • Analyzed cytokine production, p38 MAPK phosphorylation, endocytosis, and exocytosis patterns.
  • Investigated TLR2/1 dependency using TLR1 rs5743618 (1805G/T) SNP as a marker.

Main Results:

  • Mtb LAM did not induce classical PMN priming phenotypes (NADPH oxidase, l-selectin, CD11b) unlike Pam3CSK4 and FSL-1.
  • Mtb LAM elicited pro- and anti-inflammatory cytokine production via TLR2/1 signaling.
  • Mtb LAM did not induce p38 MAPK phosphorylation or endocytosis, processes essential for Pam3CSK4-induced priming.
  • Differential exocytosis patterns were observed between Mtb LAM and Pam3CSK4 stimulation.

Conclusions:

  • Mtb LAM activates PMN through TLR2/1, leading to cytokine release but not conventional early priming.
  • The distinct lack of priming by Mtb LAM may stem from differential localization of TLR2/1 signaling pathways.
  • Understanding these differential responses is key to comprehending Mtb pathogenesis and host-innate immunity.

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