immune

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Immune

Innate immune response to wounding, modeling neutrophil infiltration and macrophage recruitment with M1/M2 polarization.

Biology

The innate immune response is the first cellular reaction to wounding. Neutrophils arrive within hours as first responders, producing pro-inflammatory cytokines and clearing debris. Macrophages follow, initially in a pro-inflammatory M1 state that sustains inflammation. As the wound stabilizes, macrophages transition to an anti-inflammatory M2 state that resolves inflammation and produces growth factors (TGF-beta, VEGF) to drive tissue repair. This M1 to M2 transition is a critical checkpoint: delayed or failed transition leads to chronic inflammation and impaired healing.

Cytokine production uses age-dependent exponential tapers rather than flat rates. Neutrophils produce at cytokine_rate * exp(-taper * age), so young neutrophils at the wound site are the most active producers while NF-kB signaling declines as they age toward apoptosis. M1 macrophages produce at cytokine_rate * exp(-taper * state_age), so output declines with time in the M1 state. The inflammation peak-and-decay timecourse emerges from the interplay of these individual cell tapers with population dynamics.

Efferocytosis (phagocytosis of apoptotic neutrophils) is a key M1 to M2 transition trigger. M1 macrophages search for dying neutrophils via ForEachNeighbor; on detection, the neutrophil is engulfed and the macrophage transitions to M2.

Model

Agent-based immune cells with two types (Neutrophil, Macrophage) and macrophage states (M1, M2).

Neutrophil behavior:

• Spawn in waves (default 3 over 24h) starting at neutrophil_spawn_delay_h post-wound
• Age-dependent cytokine production with exponential taper
• After neutrophil_min_survival_h, stochastic apoptosis at neutrophil_apoptosis_rate
• Hard ceiling at neutrophil_lifespan_h

Macrophage behavior:

• Continuous recruitment driven by inflammation: spawn probability = spawn_rate * max(0, infl - threshold) * max(0, 1 - n_mac / capacity)
• Carrying capacity models limited ICAM-1 adhesion sites at postcapillary venules
• M1 state: pro-inflammatory cytokine production with age taper
• M1 to M2 transition triggers: (1) inflammation below m1_transition_threshold with min age, (2) efferocytosis of dying neutrophil, (3) macrophage_m1_duration_h ceiling fallback
• M2 state: actively consumes inflammation from the field at resolution_rate
• M2 macrophages also produce TGF-beta and VEGF

Chemotaxis: When enabled, immune cells follow the inflammation gradient via BioDynaMo's DiffusionGrid::GetGradient(). Falls back to geometric wound-center migration when gradient is flat.

Parameters

From modules/immune/config.toml:

Parameter	Default	Units	Description	Source
cell_diameter	3.0	um	Neutrophil/macrophage diameter	Convention
neutrophil_spawn_delay_h	2	hours	Hours post-wound	Kim et al. 2008 (DOI)
neutrophil_spawn_waves	3	count	Recruitment waves	Calibrated
neutrophil_spawn_window_h	24	hours	Time span for all waves	Calibrated
neutrophil_lifespan_h	48	hours	Hard ceiling	Wilgus et al. 2013
neutrophil_min_survival_h	12	hours	Min before apoptosis possible	Calibrated
neutrophil_apoptosis_rate	0.0029	per step	Death probability (half-life ~24h)	Wilgus et al. 2013
macrophage_spawn_delay_h	12	hours	Hours post-wound	Rodero & Khosrotehrani 2010
macrophage_spawn_threshold	0.002	a.u.	Inflammation for recruitment	Calibrated
macrophage_spawn_rate	0.8	-	Recruitment probability scaling	Calibrated
macrophage_spawn_taper	0.02	per hour	Recruitment probability decay	Calibrated
macrophage_m1_duration_h	48	hours	M1 duration ceiling	Krzyszczyk et al. 2018 (DOI)
m1_transition_threshold	0.003	a.u.	Inflammation below this triggers M1 to M2	Calibrated
m1_transition_min_age_h	36	hours	Min M1 time before transition	Krzyszczyk 2018
macrophage_lifespan_h	672	hours	Hard ceiling (28 days)	Convention
macrophage_min_survival_h	24	hours	Min before apoptosis possible	Calibrated
macrophage_apoptosis_rate	0.0008	per step	Death probability (half-life ~87h)	Lucas et al. 2010 (DOI)
cytokine_rate	0.004	per step	Inflammation per cell (before taper)	Eming et al. 2007
resolution_rate	0.020	per step	Inflammation consumed by M2	Koh & DiPietro 2011 (DOI)
migration_speed	1.5	-	Tractor force magnitude	Lammermann et al. 2008 (DOI)
efferocytosis_enabled	true	bool	Proximity-based M1 to M2	Convention
efferocytosis_radius	5.0	um	Search radius	Ravichandran 2010 (DOI)
efferocytosis_age_fraction	0.8	fraction	Neutrophil age for PS exposure	Savill et al. 1989 (DOI)
chemotaxis_enabled	true	bool	Follow inflammation gradient	Convention
chemotaxis_speed_scale	1.0	-	Gradient speed scaling	Calibrated
neutrophil_cytokine_taper	0.004	-	Exponential decay constant	Calibrated
m1_cytokine_taper	0.003	-	Exponential decay constant	Calibrated

Coupling

Reads

Field	Source module	How used
Inflammation	inflammation	Macrophage recruitment threshold, M1 to M2 gating
Biofilm	biofilm	Blocks M1 to M2 when above threshold

Writes

Field	Consumer modules	What is written
Inflammation	inflammation, scar, biofilm	Cytokine production (age-tapered)
ImmunePressure	tissue (migration/proliferation gating)	Cytokine production (mirrors inflammation, excludes DAMPs)
TGF-beta	fibroblast	M2 macrophage production
VEGF	angiogenesis	M2 macrophage production
MMP	mmp	M1 macrophage MMP-9 production

Validation

Dataset	Observable	Sources	Notes
immune_cell_kinetics	Neutrophil and macrophage counts over time	Kim 2008, Wilgus 2013, Krzyszczyk 2018, Rodero 2010, Lucas 2010	Peak day 2, decline by day 5
inflammation_timecourse	Emergent cytokine curve shape	Eming 2007, Koh 2011	Peak-and-decay from cell aging

Literature data

Reference curves for validation (full citations in SOURCES.yaml):

Dataset	File	Normalization
Immune cell kinetics	immune_cell_kinetics.csv	Peak = 1.0 per type

Raw digitized data (5 papers)

File	Source
kim2008_neutrophils.csv	Kim et al. 2008
wilgus2013_neutrophils.csv	Wilgus et al. 2013
krzyszczyk2018_macrophages.csv	Krzyszczyk et al. 2018
rodero2010_macrophages.csv	Rodero et al. 2010
lucas2010_macrophages.csv	Lucas et al. 2010

Metrics

Column	Units	Description
n_neutrophils	count	Active neutrophil agents
n_macrophages	count	Active macrophage agents

Source files

File	Purpose
immune_cell.h	ImmuneCell agent with type (Neutrophil/Macrophage) and state (M1/M2)
neutrophil_behavior.h	Neutrophil lifecycle: spawn, cytokine production, apoptosis
macrophage_behavior.h	Macrophage lifecycle: M1/M2 polarization, efferocytosis, TGF-beta/VEGF
immune_response.h	Immune response orchestrator: spawn timing, wave scheduling
immune_helpers.h	Cytokine production and resolution helper functions
config.toml	Module configuration