Interleukin-15-dependent NKp46+ innate lymphoid cells control intestinal inflammation by recruiting inflammatory monocytes.
With the goal in mind to define how interleukin-15 (IL-15) contributes to acute intestinal inflammation, we have used a mouse model of ileitis induced by oral infection with Toxoplasma gondii. We observed that a crosstalk between IL-15 and interleukin-18 (IL-18) promoted intestinal recruitment of inflammatory monocytes, where these cells participated in parasite control but also in tissue damage. A stromal source of IL-15 controlled the development of lamina propria NKp46(+)NK1.1(+) cells, whereas IL-18 produced during T. gondii infection stimulated their production of the chemokine CCL3. In turn, CCL3 attracted inflammatory monocytes via their chemokine receptor CCR1, which was indispensable for their recruitment into the inflamed gut. Collectively, these results identify the IL-15-dependent subset of intestinal NKp46(+) cells as an important source of CCL3, which can amplify intestinal inflammation via the recruitment of CCR1(+) inflammatory monocytes. Preliminary evidence suggests that this pathway might operate in Crohn's disease.
INSERM, U989, 75015 Paris, France; Université Paris Descartes, Paris Sorbonne Cité, Institut Imagine, France.
Julie
J
Schulthess
Bertrand
B
Meresse
Emma
E
Ramiro-Puig
Nicolas
N
Montcuquet
Sylvie
S
Darche
Bernadette
B
Bègue
Frank
F
Ruemmele
Christophe
C
Combadière
James P
JP
Di Santo
Dominique
D
Buzoni-Gatel
Nadine
N
Cerf-Bensussan
D000293:Adolescent; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000378:metabolism; D002648:Child; D003424:Crohn Disease / Q000276:immunology / Q000378:metabolism; D004751:Enteritis / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism*; D054389:Receptors, CCR1 / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology / Q000378:metabolism
D000950:Antigens, Ly; D054405:Chemokine CCL3; D019409:Interleukin-15; D020382:Interleukin-18; D053699:Interleukin-7 Receptor alpha Subunit; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D054389:Receptors, CCR1