Table 1.

Summary of TREM2 links to human disease and animal models of disease

Disease	Observation or model	Phenotype	Possible role of TREM2	Reference:
Neurodegenerative disease
Nasu-Hakola Disease	NHD patient	TREM2 mutations co-segregate with NHD	TREM2 mutations cause NHD	[7]
	Osteoclast maturation from PBMCs	Monocytes from NHD TREM2 carriers have impaired osteoclast differentiation.	TREM2 involved in myeloid maturation	[10, 89]
	Osteopenic mice	Reduced proliferation of osteoclast precursors, accelerated osteoclast maturation and apoptosis.	Myeloid proliferation and survival	[117]
Alzheimer’s disease Genetic links	Sequencing & GWAS studies	First two studies to identify a link between TREM2 variants and AD	R47H is a risk variant. Others possible.	[4, 5]
		TREM2 R47H correlated with CSF tau and p-tau	R47H is an AD risk variant	[18]
		R47H did not fully explain TREM2 disease risk	R62H is an AD risk variant	[3]
Alzheimer’s disease  Aβ Models	APPPS1 mice	Decreased number and size of plaque-associated microglia in Trem2 heterozygotes. No change in total Aβ.	Microgliosis	[47]
	5XFAD mice	Trem2−/− mice have Increased Aβ and impaired microglial response at 8mo. Decreased microglial survival.	Microglia survival, microgliosis. Protective in Aβ	[30]
	5XFAD, APPPS1 mice	5XFAD Trem2−/− mice have fewer microglia (8mo) and less plaque clustering (4,8mo), producing diffuse plaque morphology and increased neuronal pathology. No change in total Aβ.	Microgliosis, microglial proliferation. Protective in Aβ	[42]
	APPPS1 mice	Trem2−/− mice have reduced Aβ plaque burden at 4mo. Decreased plaque clustering of Iba1+ cells.	Plaque response. Possible role in proliferation, survival, and/or trafficking Detrimental in Aβ	[31]
	5XFAD, CRND8, APPPS1 mice Human R47H carrier samples	TREM2 is required for microglial barri er function around Aβ plaques. Human R47H carriers mirror Trem2 haploinsufficient mice.	Microgliosis and protective plaque response	[45]
	APPPS1 mice	TREM2 increases amyloid burden early, but reduces Aβ burden late in disease.	Microglial/myeloid proliferation, inflammation, and plaque response	[43]
	APPswe/PS1dE9 mice	In vivo overexpression reduced plaque load and inflammation.	Anti-inflammatory, Phagocytosis of Aβ	[32]
	APPswe/PS1dE9 mice	Overexpressing Trem2 in old mice (18mo) had no effect on AD pathology.	Age-restricted protective role	[146]
Alzheimer’s disease Tau models	P301S mice	Trem2 overexpression ameliorated tau pathology.	Protective, anti-inflammatory	[50]
	P301S mice	Lentiviral knockdown increased tau pathology.	Protective, anti-inflammatory	[51]
Multiple Sclerosis	Cuprizone	TREM2 sustains microglia during aging and cuprizone challenge. Reduces myelin debris.	Microglial survival and proliferation during aging myelin response	[65]
	Cuprizone	Trem2−/− mice have increased myelin debris, decreased microglial proliferation and activation.	Microgliosis and proliferation	[64]
	EAE	Antibody blockade of TREM2 signaling exacerbates symptoms.	Beneficial in MS	[126]
	EAE	EAE symptoms were reduced by Trem2-transduced macrophages.	Anti-inflammatory, protective	[152]
Prion Pathogenesis	Prion infection	No effect on prion pathogenesis, but reduced microglial activation.	Microgliosis and proliferation	[66]
Cardiovascular disease
Stroke	Experimental Ischemia	Trem2−/− mice had increased infarction, decreased microglia activation, and fewer phagocytic microglia.	Microgliosis and phagocytosis Protective following stoke	[39]
	Experimental Ischemia	Trem2−/− mice have fewer microglia at glial scars and decreased microglial activation. No change in scar size.	Microgliosis	[67]
Chronic pulmonary disease
Viral-induced COPD	SeV-induced chronic airway disease	Trem2−/− mice have reduced macrophage expansion which reduced chronic disease. IL-13 stimulation produces sTREM2 which prevents macrophage apoptosis.	Survival and proliferation. sTREM2 prevents macrophage apoptosis, allowing conversion to alternatively activated macrophages, which promote airway disease	[71]
Wound Healing
Colon injury	Chemical colon injury	Trem2−/− mice had reduced inflammation and wound damage.	Inflammatory, bacterial killing.	[73]
	Biopsy injury	TREM2 required for wound healing and promotes M2 phenotype	Promote anti-inflammatory M2 phenotype	[72]
Infection
Animal infection	E. coli endotoxemia.	TREM2 was protective in sepsis infection.	Phagocytic, anti-inflammatory	[153]
	LPS and E. coli endotoxemia.	Trem2−/− mice had increased early inflammation and faster resolution.	Phagocytic. Anti-inflammatory.	[154]
	P. aeruginosa	TREM2 activated PI3K/Akt pathway to control inflammation.	Anti-inflammatory	[155]
	S. pneumoniae	TREM2 decreased C1q expression in alveolar macrophages and TREM2 was detrimental to survival in intranasal challenge.	Anti-phagocytic, pro-inflammatory in AMs. Opposite results in BMDMs	[150]
In vitro cellular infection	P. aeruginosa	TREM2 increased ROS production through Akt/PI3K pathway. No change in phagocytosis.	Bacterial killing	[76]
	S. Typhimurium	TREM2/DAP12 required for ROS response following Salmonella infection.	Bacterial killing	[75]
	B. abortus	TREM2 inhibited NO production and increased bacterial load.	Promotes bacterial growth	[77]

Key:

5XFAD = transgenic for mutant human APP K670N/M671L + I716V+ V717I and PSEN1 M146L+ L286V

APPPS1 = transgenic for mutant human transgenes APP KM670/671NL and PSEN1 L166P

APPswe/PS1dE9 = transgenic for mutant human APP KM670/671NL and PSEN1 delta exon 9

CRND8 = transgenic for mutant human APP KM670/671NL+V717F

EAE = experimental autoimmune encephalomyelitis

P301S = Tau P301S transgenic mice

SeV = Sendai virus