Neutropenic Mice Provide Insight into the Role of Skin-Infiltrating Neutrophils in the Host Protective Immunity against Filarial Infective Larvae.
Our knowledge and control of the pathogenesis induced by the filariae remain limited due to experimental obstacles presented by parasitic nematode biology and the lack of selective prophylactic or curative drugs. Here we thought to investigate the role of neutrophils in the host innate immune response to the infection caused by the Litomosoides sigmodontis murine model of human filariasis using mice harboring a gain-of-function mutation of the chemokine receptor CXCR4 and characterized by a profound blood neutropenia (Cxcr4(+/1013)). We provided manifold evidence emphasizing the major role of neutrophils in the control of the early stages of infection occurring in the skin. Firstly, we uncovered that the filarial parasitic success was dramatically decreased in Cxcr4(+/1013) mice upon subcutaneous delivery of the infective stages of filariae (infective larvae, L3). This protection was linked to a larger number of neutrophils constitutively present in the skin of the mutant mice herein characterized as compared to wild type (wt) mice. Indeed, the parasitic success in Cxcr4(+/1013) mice was normalized either upon depleting neutrophils, including the pool in the skin, or bypassing the skin via the intravenous infection of L3. Second, extending these observations to wt mice we found that subcutaneous delivery of L3 elicited an increase of neutrophils in the skin. Finally, living L3 larvae were able to promote in both wt and mutant mice, an oxidative burst response and the release of neutrophil extracellular traps (NET). This response of neutrophils, which is adapted to the large size of the L3 infective stages, likely directly contributes to the anti-parasitic strategies implemented by the host. Collectively, our results are demonstrating the contribution of neutrophils in early anti-filarial host responses through their capacity to undertake different anti-filarial strategies such as oxidative burst, degranulation and NETosis.
Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle, CNRS; CP52, Paris, France.|UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Nicolas
N
Pionnier
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Emilie
E
Brotin
Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle, CNRS; CP52, Paris, France.
Gregory
G
Karadjian
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.|US31-UMS3679 -Plateforme PLAIMMO, Institut Paris-Saclay d'Innovation Thérapeutique (IPSIT), Inserm, CNRS, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
Patrice
P
Hemon
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.|US31-UMS3679 -Plateforme PLAIMMO, Institut Paris-Saclay d'Innovation Thérapeutique (IPSIT), Inserm, CNRS, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
Françoise
F
Gaudin-Nomé
Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle, CNRS; CP52, Paris, France.
Nathaly
N
Vallarino-Lhermitte
Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle, CNRS; CP52, Paris, France.
Adélaïde
A
Nieguitsila
Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle, CNRS; CP52, Paris, France.
Frédéric
F
Fercoq
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Marie-Laure
ML
Aknin
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Viviana
V
Marin-Esteban
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Sylvie
S
Chollet-Martin
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Géraldine
G
Schlecht-Louf
UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart and Châtenay-Malabry, France.
Françoise
F
Bachelerie
Unité Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245), Sorbonne Universités, Muséum National d'Histoire Naturelle, CNRS; CP52, Paris, France.
Coralie
C
Martin
D000818:Animals; D004195:Disease Models, Animal; D005368:Filariasis / Q000469:parasitology* / Q000473:pathology*; D005370:Filarioidea / Q000254:growth & development / Q000276:immunology*; D007113:Immunity, Innate; D007814:Larva / Q000254:growth & development / Q000276:immunology; D047589:Leukocyte Reduction Procedures; D051379:Mice; D009504:Neutrophils / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000469:parasitology* / Q000473:pathology*
C514936:CXCR4 protein, mouse; D019718:Receptors, CXCR4