NLRP6 negatively regulates type 2 immune responses in mice

Area of Science:

• Immunology
• Molecular Biology

Background:

• Inflammasomes are cytosolic protein complexes crucial for innate immunity, triggering cell death and releasing pro-inflammatory cytokines like IL-1β and IL-18.
• The NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is vital for IL-18 secretion and maintaining homeostasis, particularly in the gut.
• The role of NLRP6 in type 2 lung inflammation, such as allergic responses, has not been fully elucidated.

Purpose of the Study:

• To investigate the role of the NLRP6 inflammasome in type 2 lung inflammation.
• To determine NLRP6's influence on immune cell responses and cytokine production in allergic airway inflammation models.

Main Methods:

• Utilized wild-type (WT) and Nlrp6 knockout (Nlrp6^-/-) mice.
• Induced allergic lung inflammation using birch pollen extract (BPE) and assessed immune responses, including eosinophil recruitment, Th2 cytokine production, and airway hyperresponsiveness.
• Evaluated responses to Nippostrongylus brasiliensis (Nb) infection, including parasite expulsion and type 2 immune cell populations in the lungs.

Main Results:

• Nlrp6^-/- mice exhibited mixed Th2/Th17 immune responses with increased eosinophils, ILC2, Th2, and Th17 cells, alongside reduced IL-18 production following birch pollen challenge.
• Absence of NLRP6 led to enhanced early expulsion of Nippostrongylus brasiliensis, indicating a heightened type 2 immune response.
• In vitro studies demonstrated that NLRP6 suppresses Th2 polarization, evidenced by increased Th2 cytokines and GATA3 expression in Nlrp6^-/- cells.
• Administration of exogenous IL-18 partially ameliorated airway inflammation in Nlrp6^-/- mice.

Conclusions:

• NLRP6 functions as a negative regulator of type 2 immune responses.
• These findings highlight NLRP6's critical role in modulating allergic lung inflammation and host defense mechanisms against helminth infections.