Table 1.
Animal models with genetic disruption in specific clock components and their effects on processes related to innate immune functions and inflammation.
| Genotype | Immune Challenge | Effects | Refs. |
|---|---|---|---|
| Bmal1−/− mice (global KO) | Lost daily rhythms in the circulating numbers of white blood cells and their progenitors | [43,54] | |
| Bmal1−/− mice (global KO) | KLA (in vitro) | Disturbed transcriptome response to TLR4 activation in BMDMs (enhanced and prolonged response of Il-1β, iNos and Hif1α) | [55] |
| Bmal1−/− mice (global KO) | ↑ severity of DSS-induced colitis | [56] | |
|
ArntlLoxP/LoxPLyz2Cre mice (myeloid-specific Bmal1 KO) |
Lost daily variability in Ly6Chigh monocyte counts in the blood, spleen, and bone marrow | [52] | |
|
ArntlLoxP/LoxPLyz2Cre mice (myeloid-specific Bmal1 KO) |
TG-induced peritoneal inflammation |
↑ peritoneal recruitment of Ly6Chigh monocytes and amplified CCL2, CCL8, IL-1β, and IL-6 response | [52] |
|
ArntlLoxP/LoxPLyz2Cre mice (myeloid-specific Bmal1 KO) |
Listeria monocytogenes infection |
↓ survival and ↑ serum levels of IL-1β, IL-6, IFNγ, and CCL2 | [52] |
|
Bmal1−/−Lys-MCre mice (myeloid-specific Bmal1 KO) |
LPS 25 mg/kg (i.p.) | Lost protection to LPS-induced lethality at ZT0 compared to ZT12 | [57] |
|
Bmal1−/−Lys-MCre mice (myeloid-specific Bmal1 KO) |
LPS 100 ng/mL (in vitro) | ↑ LPS-induced production of IL-6, TNFα, CXCL1 and CCL2 and ↓ levels of IL-10 in BMDMs ↑ pro-inflammatory microRNA miR-155 induction upon LPS in BMDMs |
[57] |
|
Bmal1LoxP/LoxPLyz2Cre mice (myeloid-specific Bmal1 KO) |
LPS 100 ng/mL (in vitro) or LPS 5 mg/kg (i.p.) |
↓ NRF2 response in LPS stimulated BMDMs ↑ basal and LPS stimulated ROS levels, ↑ LPS stimulated IL-1β and HIF1α levels in BMDMs ↑ serum IL-1β response to in vivo LPS stimulation |
[58] |
|
Bmal1FloxP/FloxP;LysMCre mice (myeloid-specific Bmal1 KO) |
LPS 10 or 100 ng/mL (in vitro) | Lost daily variability in IL-12p40-producing cells in LPS-stimulated peritoneal macrophages | [59] |
|
LysM-Bmal1−/− mice (myeloid-specific Bmal1 KO) |
Streptococcus pneumoniae or Staphylococcus aureus infection | Protection against pneumococcal infection ↑ phagocytic activity in peritoneal and alveolar macrophages |
[60] |
|
LysM-Bmal1−/− mice (myeloid-specific Bmal1 KO) |
LPS 1 mg/kg (i.p.) | Lost daily variability in IL-6 response to LPS in peritoneal macrophages | [51] |
|
BmallLoxP/LoxPLyz2Cre mice (ApoE−/− background) (myeloid-specific Bmal1 KO) |
↑ size of atherosclerotic lesions ↑ recruitment of Ly6Chigh monocytes and accumulation of pro-inflammatory M1 macrophages in atherosclerotic lesions |
[61] | |
|
Bmal1ΔN mice (neutrophil-specific deletion of Bmal1) |
Lost daily variability in neutrophil proteome, granule content and NET formation | [62] | |
| Clock−/− mice (global KO) | TNFα 2 ng/mL or CBLB502 100 ng/mL (in vitro) |
↓ NF-κB activation upon TNFα treatment in MEFs and upon bacterial flagellin (CBLB502) treatment in hepatocytes | [49] |
| Clock mutant mice | LPS 1 µg/mL or S. Typhimurium (in vitro) |
↓ expression of pro-inflammatory genes Il-6, Il-1β, Tnfα, Cxcl1, Ifnβ, and Ccl2 and ↓ TNFα and IL-6 response in BMDMs | [63] |
| Clock mutant mice | Salmonella infection (in vivo) | Impaired rhythmicity in bacterial colonization in the gut and reduced pro-inflammatory gene expression | [63] |
| Clock mutant mice | LPS 1 µg/mL (in vitro) | ↓ LPS-induced expression of Il-6, Il-1β and Cxcl1 in MEFs ↑ RELB and p100/52 protein levels in MEFs independent of LPS |
[64] |
| Per1tm1Drw mutant mice | Modified circadian rhythms of perforin, granzyme B and IFNγ in the splenic NK cells | [65] | |
| mPer2Brdml mutant mice | Lost daily IFNγ rhythms (splenic mRNA and protein expression, and serum levels) in the spleen | [66] | |
| mPer2Brdml mutant mice | LPS 25 mg/kg (i.p.) | ↑ survival upon lethal dose of LPS and suppressed daily rhythm in susceptibility to endotoxic shock ↓ serum IFNγ and IL-1β levels and ↓ IFNγ production by splenic NK cells in response to LPS |
[67] |
| mPer2Brdml mutant mice | TLR9 ligand (in vitro) | ↓ TNFα and IL-12 production in challenged peritoneal macrophages and ↓ Tlr9 expression | [68] |
| Cry1−/−Cry2−/− mice and fibroblasts (double KO) | Constitutive activation NF-κB via PKA signaling in fibroblasts ↑ constitutive expression of pro-inflammatory molecules in the hypothalamus and fibroblasts (Il-6, Tnfα and iNos), and in the BMDMs (Il-6, Cxcl1 and iNos) ↑ inflammatory response of BMDMs to LPS (TNFα and IL-6) |
[69] | |
| Rev-erbα−/− mice (global KO) | LPS 1 mg/kg (i.p.) LPS 1 µg/mL (in vitro) |
Lost circadian response of IL-6 to LPS challenge in vivo and in vitro using isolated PECs | [51] |
| Rev-erbα−/− mice (global KO) | aerosolized LPS 2 mg/mL | ↑ neutrophil numbers and CXCL1, CXCL2 and CXCL5 levels in BAL fluid | [70] |
| Rev-erbα−/− mice (global KO) | LPS 100 ng/mL (ex vivo) | ↑ cytokine and chemokine response to LPS (Il-6, Ccl2 and Ccl5 expression) in alveolar macrophages | [70] |
| Rev-erbα−/− mice (global KO) | LPS 1 µg/mL (in vitro) | ↑ basal and LPS-stimulated Ccl2 gene expression in peritoneal macrophages | [71] |
| Rev-erbα−/− mice (global KO) | ↑ basal NF-κB signaling and pro-inflammatory microglial activation in the hippocampus ↑ LPS-induced neuroinflammation |
[72] | |
| Rev-erbα−/− mice (global KO) | ↑ complement transcripts (C4b and C3) in the hippocampus | [73] | |
| Rev-erbα−/− mice (global KO) | DSS-induced colitis | ↑ severity of DSS-induced colitis ↑ colonic levels of NLRP3, IL-1β, and IL-18 in DSS-induced colitis suppressed daily rhythm of Nlrp3 in the colon |
[56] |
| Rev-erbα−/− mice (global KO) | LPS 100 ng/mL (in vitro) | ↑ LPS-induced protein levels of NLRP3 and IL-1β in peritoneal macrophages | [56] |
| staggerer (RORαsg/sg) mice | intra-tracheal LPS 2 µg/50 µL | ↑ susceptibility to LPS-induced airway inflammation ↑ neutrophil counts and cytokine levels IL-1β, IL-6, and MIP-2 in BAL fluid |
[74] |
| staggerer (RORαsg/sg) mice | LPS 5 µg/mL (in vitro) | ↑ Il-1β, Il-1α, and Tnfα expression in LPS-stimulated splenocytes | [75] |
| Nfil3−/− mice (global KO) | Lack of CD8α+ cDC population in the lymphoid organs | [76] | |
| Nfil3−/− mice (global KO) | Lack of NK cells and impaired NK-cell mediated cytotoxicity | [77] | |
| Nfil3−/− mice (global KO) | Clostridium difficile infection | ↓ numbers of innate lymphoid cells in the intestinal mucosa ↓ immune defence against acute intestinal bacterial infection with Clostridium difficile |
[78] |
| Nfil3−/− mice (global KO) | LPS 10 ng/mL (in vitro) | ↑ LPS-induced Il-12b expression and IL-12p40 release from BMDMs Spontaneous expression of Il-12b in colonic CD11b+ LPMCs |
[79] |
| Nfil3−/− mice (global KO) | LPS 10 ng/mL (in vitro) | ↑ proportion of IL-12p40 producing macrophages in response to LPS and ↑ expression of Ccr2 in unstimulated BMDMs | [59] |
APOE—apolipoprotein E; BAL-bronchoalveolar lavage; BMDMs—bone marrow-derived macrophages; CCL2/5/8—CC motif chemokine ligand 2/5/8; cDC—conventional dendritic cells; CXCL1/2/5—CXC motif chemokine ligand 1/2/5; DSS—dextran sulphate sodium; HIF1α—hypoxia-inducible factor 1α; IFNγ—interferon gamma; IL—interleukin; iNOS—inducible nitric oxide synthase; KLA—Kdo2-lipid A (TLR4 ligand); KO—knock-out; LPMCs—lamina propria mononuclear cells; LPS—lipopolysaccharide; MEFs—mouse embryonic fibroblasts; MIP-2—macrophage inflammatory protein 2; NET—neutrophil extracellular trap; NF-κB—nuclear factor kappa B; NLRP3—NOD-like receptor family pyrin domain containing 3; NRF2—nuclear factor-like 2; PECs—peritoneal exudate cells; PKA—protein kinase A; RELB—subunit of nuclear factor kappa B; ROS—reactive oxygen species; TG—thioglycolate; TLR—toll-like receptor; TNFα—tumor necrosis factor alpha; ZT—zeitgeber time.